Mu opioid receptor: a gateway to drug addiction
Introduction
Drug addiction is a chronic relapsing disorder that results from gradual adaptations of the brain to repeated drug exposure. The current understanding of this complex phenomenon is that neurons responding to natural reinforcers such as food, sex, and social interactions are abnormally stimulated, leading to strong deregulations of brain reward pathways [1] and aberrant learning processes [2]. Addiction has many faces, including initiation and maintenance of drug consumption, withdrawal episodes, protracted abstinence, and relapse. Animal models for different aspects of drug-seeking behaviors have been successfully developed, and efforts are made to comprehend the transition between drug use and drug abuse [3•]. The brain circuits of addiction involve reward pathways, in association with stress, obsessive-compulsive, and habit-forming systems [4•], and molecular adaptations to chronic drug use are being actively examined in this broad neural network. Many neurotransmitter systems are recruited during these processes, with dopaminergic systems being important and the most frequently studied (see Bonci et al. [5] and references therein). The endogenous opioid system is also a major player in addiction.
Because the opioid system plays a central part in modulating mood and well being, it is believed that modifications of endogenous opioids participate in the development of drug abuse. In addition, the opioid system could also influence drug craving and relapse by altering stress physiology. Both pharmacological and genetic experimental manipulations of the opioid system support these views and demonstrate that endogenous opioids influence reinforcement and adaptations to many drugs of abuse [4•]. The opioid system consists of three G protein-coupled receptors, mu, delta, and kappa, which are stimulated by a family of endogenous opioid peptides [6]. Opioid receptors can also be activated exogenously by alkaloid opiates, the prototype of which is morphine. The finding that morphine’s analgesic and addictive properties are abolished in mice lacking the mu opioid receptor has unambiguously demonstrated that mu receptors mediate both the therapeutic and the adverse activities of this compound [7]. Importantly, a series of studies has shown that the reinforcing properties of alcohol, cannabinoids, and nicotine — each of which acts at a different receptor — are also strongly diminished in these mutant mice [8]. The genetic approach therefore highlights mu receptors as convergent molecular switches, which mediate reinforcement following direct (morphine) or indirect activation (non-opioid drugs of abuse; see Figure 1). Beyond the rewarding aspect of drug consumption, pharmacological studies have also suggested a role for this receptor in the maintenance of drug use, as well as craving and relapse [4•]. As a consequence, expanding our understanding of mu receptor function should greatly help to further our knowledge of the general mechanisms that underlie addiction.
This review focuses on recent findings regarding cellular regulation of mu receptors in the neuron and molecular mechanisms of responses to mu receptor activation in vivo. The latter part describes several genes involved in mu receptor signaling, highlights the implicated brain structures and summarizes initial results from genomic approaches.
Section snippets
Regulation of mu receptor signaling in neurons: an agonist-dependent process
Opioid agonists binding at mu receptors modulate intracellular effectors through inhibitory Go/Gi proteins. Receptor signaling, in turn, is readily terminated by several cellular regulatory processes that include phosphorylation, desensitization, endocytosis, and downregulation. An important observation from signaling and trafficking studies in transfected cells is that mu receptor activation and subsequent regulations are strongly agonist-dependent. Therefore, the agonist–receptor complex,
Molecular adaptations to mu receptor activation in vivo: genetic approaches
Among mu agonists, morphine is most relevant both in terms of clinical use (pain treatment) and in abuse potential (heroin addiction). Morphine essentially activates mu receptors in vivo, and the effects of chronic morphine exposure in whole animals reflect the consequences of repeated mu receptor activation in the nervous system. The analysis of morphine responses in about 30 genetically modified animals has recently revealed many partners of mu receptor signaling in vivo. In Table 1, we have
Mu receptor-activated neural circuits: functional mapping
Mu receptors are broadly expressed in all brain areas belonging to the circuits of addiction (Figure 2). These include mesolimbic dopaminergic neurons, which originate from the VTA and project to the nucleus accumbens. These neurons have been widely studied in the past few years. The nucleus accumbens itself is part of a complex network that includes prefrontal cortical areas, hippocampus, and basal forebrain structures known as the extended amygdala. The extended amygdala is formed by a
Novel approaches to study mu receptor signaling and molecular adaptations to morphine in vivo
To complement candidate gene approaches several screening methods are now being developed to better understand the consequences of mu receptor activation. The yeast two-hybrid system has identified proteins that physically interact with the carboxy-termini of mu receptors and regulate distinct aspects of mu receptor activity at the cellular level. Phospholipase D2 was found to associate with the mu receptor in the plasma membrane of transfected HEK cells, and accelerated agonist-induced
Conclusions
Recent basic research has first, explored cellular mechanisms that regulate mu receptor activity in neurons, second, identified several genes associated with mu receptor signaling in vivo and third, revealed the crucial role of neuronal activation in the extended amygdala following mu receptor activation. Mu receptor signaling is activated by several drugs of abuse (opioid and non-opioid) and therefore represents a potential target for the therapeutics of addiction. In the clinic, strategies
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
Acknowledgements
The authors wish to thank the Human Frontier Science Program, the Mission Interministérielle de Lutte contre la Drogue et la Toxicomanie and the National Institute of Health (NIH-NIDA #DA05010; NIAAA#AA13481) for financial support. They also thank LA Karchewski for helpful advice.
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